WO2019112031A1 - Agent thérapeutique de la sclérodermie systémique - Google Patents

Agent thérapeutique de la sclérodermie systémique Download PDF

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WO2019112031A1
WO2019112031A1 PCT/JP2018/045053 JP2018045053W WO2019112031A1 WO 2019112031 A1 WO2019112031 A1 WO 2019112031A1 JP 2018045053 W JP2018045053 W JP 2018045053W WO 2019112031 A1 WO2019112031 A1 WO 2019112031A1
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expression
scleroderma
compound
evaluation
collagen
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PCT/JP2018/045053
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Japanese (ja)
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雅巳 大塚
眞一郎 丹羽
大 小倉
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サイエンスファーム株式会社
リンク・ジェノミクス株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to a preventive and therapeutic agent for systemic scleroderma (SSc). More specifically, the present invention relates to an agent for suppressing and / or treating fibrosis, which is a pathological condition of systemic scleroderma.
  • SSc systemic scleroderma
  • Systemic scleroderma causes fibrosis in the skin dermis, movement disorders due to restricted movement of the limbs / contracture, necrosis in the peripheral area due to ulceration, etc., and the QOL of the patient is significantly reduced, and the lung fibers are advanced by progress.
  • SSc therapeutic agents drugs that suppress inflammation, such as immunosuppressants, steroids, and traditional Chinese medicines, are mainly used, but all of them are symptomatic therapeutic drugs and there is no cure that can be cured.
  • pulmonary antihypertensive agent bosentan Actelion Pharmaceuticals
  • its efficacy is limited, for example, to suppress the onset of finger ulcers, and no therapeutic effect on SSc has been observed.
  • a pharmaceutical composition for treating or preventing systemic scleroderma which comprises a compound that inhibits fibroblast activation in a tissue derived from dermis.
  • a pharmaceutical composition for treating or preventing systemic scleroderma which comprises a compound that inhibits fibroblast activation in a tissue derived from dermis.
  • the above compounds are benzbromarone, albendazole, mebendazole, risedronate sodium hydrate, epalrestat, aluminum flufenamate, zaltoprofen, anlexanox, mefenamic acid, oxaprozin, and 3-[(1E) -2- (1H] -Indol-6-yl) ethenyl] -5-[(1E) -2- [2-methoxy-4- (2-pyridylmethoxy) phenyl] ethenyl] -1 H-pyrazole, selected from the above The pharmaceutical composition as described in 1] or [2].
  • inflammation is enhanced in dermal tissue of a patient with systemic scleroderma, and cells (fibroblasts) present in the tissue are activated and collagen is Secretion of the extracellular matrix, etc., and this revealed that the focal fibrosis was occurring.
  • a medicament for treating systemic scleroderma a compound that can be used for such a medicament, a method for treating systemic scleroderma using such a compound, a method for producing a medicament and A method of use is provided.
  • a compound having an inhibitory action on fibrosis which is a pathological condition of systemic scleroderma.
  • FIG. 1 shows hematoxylin and eosin (H & E) stained images of skin tissues from scleroderma (SSc) patients and healthy controls (Control).
  • FIG. 2A shows the results of immunohistochemistry (IHC) analysis of skin tissues from scleroderma patients and healthy controls (Control) using an anti- ⁇ -SMA antibody.
  • FIG. 2B shows the results of IHC analysis using anti-Fibronectin antibodies of skin tissues from scleroderma patients and healthy controls (Control).
  • FIG. 2C shows the results of IHC analysis of skin tissue from scleroderma patients and healthy controls (Control) using an anti-ZEB1 antibody.
  • FIG. 1 shows hematoxylin and eosin (H & E) stained images of skin tissues from scleroderma (SSc) patients and healthy controls (Control).
  • FIG. 2A shows the results of immunohistochemistry (IHC) analysis of skin tissues from scleroderma patients and healthy controls (Control) using an anti
  • FIG. 3 is a diagram collectively showing the results of pathological analysis and molecular dynamics analysis in the SSc sample shown in FIGS. 1 and 2A-C.
  • FIG. 4 is a graph showing the results of expression kinetic analysis of various gene groups (differentiation related markers) with respect to primary cultured fibroblasts from skin tissues derived from scleroderma patients and healthy controls (Control).
  • FIG. 5 is a graph showing the results of analysis of expression kinetics of collagen (collagen fibers) of primary culture fibroblasts from skin tissues from scleroderma patients and healthy individuals (Control).
  • FIG. 6 is a graph showing the results of expression kinetic analysis of various differentiation-related markers using healthy fibroblasts and healthy fibroblasts after inflammatory stimulation.
  • FIG. 4 is a graph showing the results of expression kinetic analysis of various gene groups (differentiation related markers) with respect to primary cultured fibroblasts from skin tissues derived from scleroderma patients and healthy controls (Control).
  • FIG. 5 is a graph
  • FIG. 7 is a graph showing the results of expression kinetic analysis of collagen (collagen fiber) using healthy fibroblasts and healthy fibroblasts after inflammatory stimulation.
  • FIG. 8A is a graph showing the evaluation results of evaluation compounds (epalrestat and oxaprozin) on the expression of various differentiation-related marker molecules by scleroderma patient-derived cells at 48 hours after the addition of the evaluation compound.
  • FIG. 8B is a graph showing the results of evaluating the suppressive effects of the evaluation compounds (anlexanox and zaltoprofen) on the expression of various differentiation-related marker molecules using scleroderma patient-derived cells 48 hours after the addition of the evaluation compounds.
  • FIG. 8A is a graph showing the evaluation results of evaluation compounds (epalrestat and oxaprozin) on the expression of various differentiation-related marker molecules by scleroderma patient-derived cells at 48 hours after the addition of the evaluation compound.
  • FIG. 8B is a graph showing the results of evaluating the suppressive effects of
  • FIG. 8C is a graph showing the results of evaluating the suppressive effects of the evaluation compounds (mefenamic acid and aluminum flufenamate) on the expression of various differentiation-related marker molecules 48 hours after the addition of the evaluation compounds using scleroderma patient-derived cells. It is.
  • FIG. 9A is a graph showing the results of evaluating the suppressive activity of epalrestat on various differentiation-related marker molecule expression 120 hours after the addition of the evaluation compound using scleroderma patient-derived cells.
  • FIG. 9B is a graph showing the results of evaluating the suppressive activity of mebendazole on the expression of various differentiation-related marker molecules 120 hours after the addition of the evaluation compound using scleroderma patient-derived cells.
  • FIG. 9A is a graph showing the results of evaluating the suppressive activity of epalrestat on various differentiation-related marker molecule expression 120 hours after the addition of the evaluation compound using scleroderma patient-derived cells.
  • FIG. 9B is a graph showing the results of
  • FIG. 9C is a graph showing the results of evaluation of suppression activity of various types of differentiation-related marker molecules of anbendazole 120 hours after addition of an evaluation compound using scleroderma patient-derived cells.
  • FIG. 10 shows the results of evaluating the inhibitory effect of an evaluation compound (Epalrestat) on collagen secretion increase (factor of fibrosis) specifically recognized in scleroderma patient skin using scleroderma patient-derived cells
  • FIG. 11A shows the results of evaluating the suppressive effects of evaluation compounds (epalrestat and oxaprodin) on the expression of various differentiation-related marker molecules by an inflammation stimulation system using fibroblasts from healthy subjects 48 hours after addition of the evaluation compounds. It is a graph.
  • FIG. 10 shows the results of evaluating the inhibitory effect of an evaluation compound (Epalrestat) on collagen secretion increase (factor of fibrosis) specifically recognized in scleroderma patient skin using scleroderma patient-derived cells
  • FIG. 11A shows the results of
  • FIG. 11B shows the results of evaluating the suppressive effect of evaluation compounds (Anlexanox and zaltoprofen) on the expression of various differentiation-related marker molecules by the inflammation stimulation system using fibroblasts from healthy subjects 48 hours after the addition of the evaluation compounds. It is a graph.
  • FIG. 11C shows that the inhibitory effect of the evaluation compounds (aluminum flufenamate and mefenamic acid) on the expression of various differentiation-related marker molecules by an inflammation stimulation system using fibroblasts from healthy subjects was evaluated 48 hours after the addition of the evaluation compounds. It is a graph which shows a result.
  • FIG. 12A is a graph showing the results of evaluating the suppressive effect of an evaluation compound (Epalrestat) on the expression of various differentiation-related marker molecules by an inflammation stimulation system using fibroblasts from healthy subjects at 120 hours after the addition of the evaluation compound. is there.
  • FIG. 12B is a graph showing the results of evaluating the suppressive effect of an evaluation compound (mebendazole) on the expression of various differentiation-related marker molecules by an inflammation stimulation system using fibroblasts from healthy subjects 120 hours after the addition of the evaluation compound. is there.
  • FIG. 12C is a graph showing the results of evaluating the suppressive effect of an evaluation compound (albendazole) on the expression of various differentiation-related marker molecules by an inflammation stimulation system using fibroblasts from healthy subjects at 120 hours after addition of the evaluation compound.
  • FIG. 13A is a diagram showing the results of evaluating the suppressive effect of an evaluation compound (epalrestat) on collagen secretion enhancement (factor of fibrosis) using an inflammation stimulation system using healthy derived fibroblasts.
  • FIG. 13B is a diagram showing the results of evaluation of the suppressive effect of an evaluation compound (mebendazole) on collagen secretion enhancement (factor of fibrosis) using an inflammation stimulation system using healthy derived fibroblasts.
  • FIG. 13C is a diagram showing the results of evaluation of the suppressive effect of an evaluation compound (albendazole) on collagen secretion enhancement (factor of fibrosis) using an inflammation stimulation system using healthy derived fibroblasts.
  • FIG. 13A is a diagram showing the results of evaluating the suppressive effect of an evaluation compound (epalrestat) on collagen secretion enhancement (factor of fibrosis) using an inflammation stimulation system using healthy derived fibroblasts.
  • FIG. 13B is a diagram showing the results of evaluation of the suppressive effect of an
  • FIG. 14 is a view schematically showing a protocol for evaluating the efficacy of suppression of fibrosis carried out using a scleroderma disease mouse model.
  • FIG. 15A is a diagram showing an H & E stained image showing the skin thickening inhibitory effect of epalrestat on skin tissue derived from a scleroderma disease model mouse established by administration of bleomycin.
  • FIG. 15B is a graph quantitatively showing the results of FIG. 15A.
  • 16A-D show 3-[(1E) -2- (1H-indol-6-yl) ethenyl] -5 against skin tissue of scleroderma disease model mouse induced by administration of bleomycin (Bleo) in Example 7.
  • FIG. 17 is a graph quantitatively showing the results shown in FIG. 16A-D.
  • FIGS. 18A-D show photographs of specimens stained with Masson's trichrome (Masson trichrome) staining in Example 7.
  • FIG. The area stained blue corresponds to the area of fibrosis.
  • the conditions of FIGS. 18A-D correspond to the conditions of FIGS. 16A-D.
  • FIG. 19 is a diagram quantitatively showing the results shown in FIG. 18A-D.
  • FIG. 20 is a diagram showing the results of an evaluation experiment (experiment A) of the inhibitory effect of compound A on the expression (mRNA) of collagens Collagen 1A2 and Fibronectin 1.
  • FIG. 21 is a diagram showing the results of an evaluation experiment (experiment B) of the inhibitory effect of compound A on the expression of collagen Collagen 1A2 protein.
  • FIG. 22 shows the results of an evaluation experiment (experiment C) of the suppressive effect of compound A on the expression of Fibronectin protein.
  • fibroblast activation refers to enhancement of ⁇ -smooth muscle actin (SMA) expression in fibroblasts (myofibroblast formation), enhancement of various collagen (collagen fibers) expression, Alteration of traits in fibroblasts characterized by enhanced expression of fibronectin, other zinc finger E box-bound homeobox 1 (ZEB1), N-cadherin (N-cadherin), enhanced expression of differentiation-related markers such as vimentin (Vimentin) It means what is characteristically found in the dermis of the skin of patients with generalized scleroderma.
  • SMA smooth muscle actin
  • “suppressing fibroblast activation” means that the expression level of differentiation-related markers such as ⁇ SMA, various collagens, fibronectin enhanced by fibroblast activation is decreased by the action of the inhibitor.
  • the expression level of the marker after reduction may not necessarily be low compared to normal cells.
  • Fibroblast activation or suppression thereof is quantified by analyzing the expression dynamics of a group of genes whose expression changes when cells are differentiated ("differentiation related markers"), as described in detail in the examples below. Can be evaluated.
  • the present invention provides a compound that inhibits fibroblast activation in a tissue derived from dermis and a composition containing the compound.
  • the present invention provides a pharmaceutical composition for treating and / or preventing systemic scleroderma, which comprises a therapeutically effective amount of a compound that inhibits fibroblast activation in dermis-derived tissues. Do.
  • the present invention provides a compound that inhibits fibroblast activation in dermis-derived tissues for use in the treatment and / or prevention of systemic scleroderma.
  • the present invention is the use (or method of use of a compound that inhibits fibroblast activation in dermis-derived tissues in the manufacture of a medicament for the treatment and / or prevention of systemic scleroderma. )I will provide a.
  • the present invention relates to a method of treating and / or preventing systemic scleroderma, which comprises administering to a patient in need thereof a compound that inhibits fibroblast activation in a dermis-derived tissue.
  • a method is provided, comprising the step of administering.
  • Specific examples of the “compound that inhibits fibroblast activation in the tissue derived from dermis” used in each of the above embodiments include benzbromarone, albendazole, mebendazole, risedronate sodium hydrate, epalrestat, flufenamic acid Aluminum, zaltoprofen, annexanox, mefenamic acid, oxaprozin, and 3-[(1E) -2- (1H-indol-6-yl) ethenyl] -5- (1E) -2- [2-methoxy-4- (2) 2-Pyridylmethoxy) phenyl] ethenyl] -1H-pyrazole, as well as their pharmaceutically acceptable salts and their derivative compounds.
  • the method for confirming the therapeutic effect of the compound of the present invention on systemic scleroderma is not particularly limited.
  • bleomycin-induced pulmonary fibrosis model mice (generally recognized as animal models for systemic scleroderma and pulmonary fibrosis) Using a mouse, for example, Curr Opin Pulm Med. 2011 Sep; 17 (5): 355-61 (G), etc.) to confirm the inhibitory effect of lesion formation.
  • the specific test method using the above-mentioned model mouse is shown in the examples described later.
  • the "pharmaceutically acceptable salts” include those which form pharmaceutically acceptable salts with the specific compounds described above, and are not particularly limited. Specifically, for example, hydrohalide (eg, hydrogen fluoride, hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid salt (eg, sulfate, nitrate, persulfate, etc.) Chlorates, phosphates, carbonates, bicarbonates, etc., organic carboxylates (eg, acetates, oxalates, maleates, tartrates, fumarates, citrates, etc.), organic sulfones Acid salts (eg, methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, camphor sulfonate, etc.), amino acid salts (eg, aspartate
  • the "derivative compound” refers to a compound which may be an equivalent of the above specific compound, and includes glycosides or esters (eg, alkyl esters such as methyl ester, ethyl ester etc.), etc. Be done.
  • confirmation about whether a derivative compound is equivalent can be performed by confirming whether it has a function which suppresses the promotion of fibroblast activation in skin dermis tissue by an above-described test.
  • the compounds of the present invention can be formulated, but not limited to, by conventional methods to provide the prophylactic and / or therapeutic agents of the present invention.
  • Preferred dosage forms of the prophylactic and / or therapeutic agent of the present invention are, for example, tablets, powders, fine granules, granules, dry syrups, coated tablets, orally disintegrating tablets, chewable tablets, capsules, soft capsules, syrups Agents, oral solutions, troches, jellies, inhalants, suppositories, injections, ointments, eye drops, eye ointments, eye drops, nasal drops, ear drops, poultices, lotions, external solutions, sprays, External aerosols, creams, gels, tapes, buccal tablets, sublingual tablets, vaginal suppositories, vaginal tablets, rectal soft capsules and the like can be mentioned.
  • excipients for example, excipients, binders, disintegrants, coatings, lubricants, coloring agents, flavoring agents and, if necessary, stabilizers, emulsifiers, absorption accelerators, surfactants, etc.
  • PH adjusting agents, preservatives, antioxidants and the like can be used, and the components generally used as raw materials of pharmaceutical preparations can be blended and formulated by a conventional method.
  • the invention also includes a method of preparing a pharmaceutical composition comprising mixing at least one carrier.
  • the components (carriers) used in the formulation are not particularly limited, and examples thereof include animal oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; and octyldodecyl myristate, for example.
  • Ester oil such as isopropyl myristate; higher alcohol such as cetostearyl alcohol, behenyl alcohol; silicone resin; silicone oil; polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxy acid Surfactants such as ethylene-cured castor oil, polyoxyethylene polyoxypropylene block copolymer; eg, hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer Water-soluble polymers such as polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; For example, inorganic powder such as anhydrous silicic acid, aluminum magnesium silicate, aluminum silicate, purified water and the like can be
  • lactose for example, lactose, corn starch, sucrose, glucose, mannitol, sorbite, crystalline cellulose, silicon dioxide etc.
  • a binder for example, polyvinyl alcohol, gelatin, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin , Shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, corn starch etc., and as a disintegrant, for example, corn starch, low substituted hydroxypropyl cellulose, crospovidone, crystalline cellulose, precipitated calcium carbonate , Croscarmellose sodium, calcium citrate, dextrin, pectin, carboxymethylcellulose calcium
  • lubricants for example, magnesium stearate, talc, polyethylene glycol, light anhydrous silicic acid, sucrose fatty acid ester
  • an oral preparation may be a compound which is an active ingredient, or a salt or ester thereof, or a hydrate thereof and an excipient, and further, if necessary, for example, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent After adding etc., it is set as a powder, a fine granule, a granule, a tablet, a coated tablet, a capsule etc. by a conventional method. In the case of tablets and granules, for example, sugar coating, etc. may of course be appropriately coated if necessary.
  • a syrup, a preparation for injection, etc. for example, a pH adjusting agent, a solubilizing agent, an isotonizing agent and the like, and a solubilizing agent, a stabilizing agent and the like as necessary, are formulated by a conventional method.
  • the manufacturing method is not particularly limited, and the external preparation can be manufactured by an ordinary method.
  • a base material to be used various raw materials usually used for medicines, quasi-drugs, cosmetics etc. can be used.
  • animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids Raw materials such as silicone oil, silicone oil, surfactant, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, acrylic adhesive clay minerals, purified water etc., and if necessary, pH adjustment Preparations, antioxidants, chelating agents, preservatives and fungicides, coloring agents, flavors and the like can be added.
  • components having differentiation-inducing action for example, components such as blood flow enhancers, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, moisturizers, keratolytic agents can also be blended. .
  • the administration mode of the prophylactic and / or therapeutic agent of the present invention is not particularly limited, and may be oral administration or parenteral administration.
  • Parenteral administration includes, for example, rectal administration, nasal administration, pulmonary administration, injection administration (eg, intravenous administration, intraspinal administration, epidural administration, intramuscular administration, subcutaneous administration, intraperitoneal administration
  • the content of the compound of the present invention contained in the preventive and / or therapeutic agent of the present invention is not particularly limited, in the subject to be administered, it exerts the effect of suppressing the enhancement of fibroblast activation in skin dermal tissue. It is preferable to use a dose sufficient for
  • the dosage of the prophylactic and / or therapeutic agent of the present invention varies depending on, for example, the degree of symptoms, age, sex, body weight, administration form, type of salt, specific type of disease, etc.
  • the compound of the present invention which is the active ingredient per day, is orally administered at about 25 mg to about 4.5 g, preferably about 75 mg to about 1.5 g, more preferably about 150 mg to about 600 mg About 25 mg to about 4.5 g, preferably about 75 mg to about 1.5 g, more preferably about 150 mg to about 600 mg, each in one or several divided doses.
  • the administration target of the prophylactic and / or therapeutic agent of the present invention is not particularly limited, but is preferably a mammal including human.
  • Mammals including humans are not particularly limited, and include, for example, humans, monkeys, baboons, chimpanzees, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, sheep, goats, pigs, cattle and horses, etc. .
  • compositions of the present invention may, if desired, be provided in the form of a kit comprising a container, such as a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the present invention can also combine separate drug compositions in kit form.
  • the kit may comprise two or more separate pharmaceutical compositions.
  • the compounds of the present invention and anti-inflammatory and / or immunosuppressive agents may be included.
  • the kit will usually include a container for containing the separate compositions, such as, for example, a split bottle or a split foil packet, but the separate compositions may also be included in a single non-split container. it can.
  • the kit form is preferably to administer the separate components in different dosage forms (e.g. orally and parenterally), when the separate components are administered at different dosing intervals, or individual components combined by the prescribing physician It is particularly useful when it is necessary to titrate.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs are generally preferred to consist of a sheet of relatively rigid material covered by a foil of transparent plastic material. During the packaging process, recesses are formed in the plastic foil. These indentations are adapted to the size and shape of the individual tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively hard material is sealed against the plastic foil in the foil plane opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is preferably such that the tablet or capsule can be removed from the blister pack by manually applying pressure to the recess such that an opening is formed in the sheet at the location of the recess. Tablets or capsules can be removed by the opening
  • the pack or dispenser device may be accompanied by package inserts, product inserts and the like for administration.
  • Containers such as packs or dispensers can be adapted to the notices of government agencies, authorities which regulate the manufacture, use or sale of medicines.
  • Another aspect of the present invention relates to a food or drink, a feed, a food additive, a feed additive or the like, which contains a compound having a function of suppressing an increase in fibroblast activation in a dermis-derived tissue.
  • the food and drink of the present invention are food additives generally used for food and drink, such as sweeteners, colorants, preservatives, thickeners, thickeners, antioxidants, color formers, bleaches, fungicides, One or more of a gum base, a bitter taste agent, an enzyme, a brightener, an acidulant, a seasoning, an emulsifier, a toughening agent, a preparation agent, a flavor, a spice extract and the like may be added.
  • the food and drink of the present invention include health food, functional food, food for specified health, food for infants, food for infants, food for pregnant women, food for elderly people, food for sick people.
  • the form of the food and drink of the present invention is not particularly limited. Specifically, for example, tablets, granules, powders, drinks and the like as so-called nutraceuticals (supplements) can be mentioned.
  • beverages such as tea beverages, soft drinks, carbonated beverages, nutritional beverages, fruit beverages, lactic acid beverages, etc., buckwheat noodles such as udon, Chinese noodles, instant noodles, etc., candy, candy, gum, chocolate, snacks , Biscuit, jelly, jam, cream, baked goods, confectionery such as bread, breads, fishery products such as kamaboko, ham, sausage, processed foods, dairy products such as processed milk, fermented milk, salad oil, tempura oil, margarine, Oils and fats processed foods such as mayonnaise, shortening, whipped cream and dressings, seasonings such as sauces and sauces, retort pouched foods such as curry, stew, chopsticks, chopsticks and risotto, frozen desserts such as ice cream, she
  • the intake amount of the food and drink of the present invention is not particularly limited, and the form of the food and drink; age, sex, condition and the like of the subject who ingests the food and drink; or the carrier carried or mixed with the carrier of the present invention You may set according to the kind of functional substance, and other conditions.
  • Biopsy sample In order to understand the fibrotic condition occurring in the patient tissue, we used the Biopsy sample to analyze the pathological condition and molecular dynamics in the lesion.
  • Skin tissues from scleroderma patients and healthy (Control) were collected. A formalin fixed paraffin block was made. These tissue samples were deparaffinized by treating with xylene 5 minutes ⁇ 3 times, 100% ethanol 1 minute ⁇ 2 times, 90% ethanol 1 minute, 80% ethanol 1 minute, 70% ethanol 1 minute, water 5 minutes . Staining was performed with Meyer's hematoxylin solution for 4 minutes and eosin solution for 1 minute. Treated in running water for 5 minutes, treated with 70% ethanol 1 minute, 80% ethanol 1 minute, 90% ethanol 1 minute, 100% ethanol 1 minute ⁇ 2 times, xylene 5 minutes ⁇ 3 times, using marinol Sealed. After drying at room temperature for 15 minutes or more, observation was performed using an optical microscope.
  • Tissue samples were deparaffinized by treating with xylene 5 minutes ⁇ 3 times, 100% ethanol 1 minute ⁇ 2 times, 90% ethanol 1 minute, 80% ethanol 1 minute, 70% ethanol 1 minute, water 5 minutes.
  • the antigen was activated by microwave treatment for 10 minutes using citrate buffer pH 6.0. After standing at room temperature for 30 minutes, treatment with PBS for 5 minutes for 5 minutes, 3% hydrogen peroxide / PBS solution for 5 minutes, and PBS for 5 minutes was performed to inactivate endogenous peroxidase.
  • the tissue was blocked by standing in a 3% BSA / PBS solution for 30 minutes at room temperature.
  • anti- ⁇ -SMA antibody DAKO # M0851
  • anti-ZEB1 antibody SantaCruz # Sc-10572
  • 4800 times dilution 200 microliter per tissue of the anti-Fibronectin antibody abcam # 45688
  • the tissue reacted with the primary antibody was washed with PBS for 5 minutes x 3 times, and then a biotin-labeled antibody of animal species suitable for the optimally diluted primary antibody was poured onto the slide and allowed to react for 30 minutes at room temperature.
  • FIG. 3 summarizes the above results. Based on these results, systemic sclera of "Scleroderma patient skin has an enhanced activation of fibroblasts in the dermis, which causes the extracellular matrix such as collagen to grow and form a fibrotic lesion".
  • RNA extract lysate was produced.
  • Total RNA was extracted from the lysate using RNeasy Micro kit (QIAGEN # 74004), and fluorescently labeled using Low Input QuickAmp Labeling kit (Agilent Technologies # 5190-2305). Labeled cRNA was hybridized to Whole Human Genome Oligo-DNA Microarray Kit (Agilent Technologies # G4112F) according to the protocol defined by the manufacturer.
  • the hybridized slides were washed using Gene Expression Wash Pack (Agilent Technologies # 5188-5327) and scanned with an Agilent Microarray Scanner (Agilent Technologies # G2505B). Scanned images were quantified using Feature Extraction software version 9.5.1 (Agilent Technologies). Numerical data were normalized by the Grobal Normalization method.
  • Labeled cRNA was hybridized to Whole Human Genome Oligo-DNA Microarray Kit (Agilent Technologies # G4112F) according to the protocol defined by the manufacturer.
  • the hybridized slides were washed using Gene Expression Wash Pack (Agilent Technologies # 5188-5327) and scanned with an Agilent Microarray Scanner (Agilent Technologies # G2505B). Scanned images were quantified using Feature Extraction software version 9.5.1 (Agilent Technologies). Numerical data were normalized by the Grobal Normalization method.
  • fibroblasts from healthy subjects are activated by inflammatory stimulation, become myofibroblasts ( ⁇ SMA expression), and expression of various differentiation-related markers is enhanced, and fibers from scleroderma patients are observed. It showed the same expression kinetics as blast cells.
  • inflammatory stimulation of normal human fibroblasts leads to increased expression of collagen, and activation of fibroblasts confirmed in scleroderma skin tissue (myofibroblast formation) collagen. Fiber growth was reproduced.
  • a compound having an inhibitory activity was obtained using an inflammatory stimulation activation model system using activated fibroblasts from scleroderma patients and healthy fibroblasts.
  • Plates were seeded with primary culture fibroblasts from scleroderma patient skin tissue and incubated at 37 ° C. The following day, an evaluation compound (test drug) was added to the culture medium to a maximum drug plasma concentration (Cmax), and cells were collected 48 hours later. As a control, a sample to which an evaluation compound was not added and a cultured fibroblast sample derived from a healthy skin tissue were used. The collected cells were washed with PBS, and 350 uL of RLT buffer was added to prepare a lysate for RNA collection.
  • RNA is extracted from the lysate using RNeasy Micro kit (QIAGEN # 74004), and cDNA is prepared from 2 ⁇ g of the obtained RNA using SuperScript III First-Strand Synthesis SuperMix for qRT-PCR (Invitrogen # 11752-250) did.
  • real-time PCR (ABI Prism 7500 Sequence Detection System) was performed according to the manufacturer's protocol, and the expression of mRNA of each gene was quantitatively analyzed.
  • Specific primers for each gene were purchased from Invitrogen.
  • Each gene Ct (Threshold Cycle) value was normalized by the endogenous control, and the ratio to the cultured fibroblast sample derived from the healthy skin tissue was calculated.
  • RNA is extracted from the lysate using RNeasy Micro kit (QIAGEN # 74004), and cDNA is prepared from 2 ⁇ g of the obtained RNA using SuperScript III First-Strand Synthesis SuperMix for qRT-PCR (Invitrogen # 11752-250) did.
  • real-time PCR (ABI Prism 7500 Sequence Detection System) was performed according to the manufacturer's protocol, and the expression of mRNA of each gene was quantitatively analyzed.
  • Specific primers for each gene were purchased from Invitrogen.
  • Each gene Ct (Threshold Cycle) value was normalized by the endogenous control, and the ratio to the cultured fibroblast sample derived from the healthy skin tissue was calculated.
  • the suppression of (the growth of collagen fibers) was observed, and the remarkable suppression effect on fibroblast activation by albendazole was observed in a concentration-dependent manner.
  • TGF- ⁇ 2 (eBioscience, 14-8368) was added to the medium to 5 ng / mL, and at the same time, the evaluation compound (test agent) was brought to the maximum drug plasma concentration (Cmax).
  • Cmax maximum drug plasma concentration
  • the cells were collected after 48 hours.
  • a non-inflammatory stimulus sample untreated
  • a sample to which an evaluation compound was not added were used.
  • the collected cells were washed with PBS, and 350 uL of RLT buffer was added to prepare a lysate for RNA collection.
  • RNA is extracted from the lysate using RNeasy Micro kit (QIAGEN # 74004), and cDNA is prepared from 2 ⁇ g of the obtained RNA using SuperScript III First-Strand Synthesis SuperMix for qRT-PCR (Invitrogen # 11752-250) did.
  • real-time PCR (ABI Prism 7500 Sequence Detection System) was performed according to the manufacturer's protocol, and the expression of mRNA of each gene was quantitatively analyzed.
  • Specific primers for each gene were purchased from Invitrogen.
  • Each gene Ct (Threshold Cycle) value was normalized by the endogenous control, and the ratio to the non-inflammatory stimulus sample (untreated) was calculated.
  • the addition of the evaluation compound suppresses the induction of expression of ⁇ SMA (myofibroblast formation) induced by inflammation stimulation, the expression induction of various collagens, and the expression induction of various differentiation-related markers.
  • ⁇ SMA myofibroblast formation
  • the inhibition was observed, and the inhibitory effect on the fibroblast activation by the evaluation compound was observed.
  • TGF- ⁇ 2 (eBioscience, 14-8368) was added to the medium to 5 ng / mL, and at the same time, evaluation compounds were added under each of 4 conditions based on Cmax, and cells were recovered after 120 hours did.
  • a non-inflammatory stimulus sample untreated
  • a sample to which an evaluation compound was not added were used.
  • the collected cells were washed with PBS, and 350 uL of RLT buffer was added to prepare a lysate for RNA collection.
  • RNA is extracted from the lysate using RNeasy Micro kit (QIAGEN # 74004), and cDNA is prepared from 2 ⁇ g of the obtained RNA using SuperScript III First-Strand Synthesis SuperMix for qRT-PCR (Invitrogen # 11752-250) did.
  • real-time PCR (ABI Prism 7500 Sequence Detection System) was performed according to the manufacturer's protocol, and the expression of mRNA of each gene was quantitatively analyzed.
  • Specific primers for each gene were purchased from Invitrogen.
  • Each gene Ct (Threshold Cycle) value was normalized by the endogenous control, and the ratio to the non-inflammatory stimulus sample (untreated) was calculated.
  • TGF- ⁇ 2 (eBioscience, 14-8368) was added to the medium to 5 ng / mL, and at the same time, evaluation compounds were added under each of four conditions based on Cmax, and cell culture was performed after 120 hours. The supernatant was collected.
  • absorbance at 555 nm was measured using Infinite M200 (TECAN).
  • a standard curve was prepared using a standard solution, the content of collagen secreted in the culture solution was calculated, and the ratio to the non-inflammatory stimulus sample (untreated) was calculated.
  • inflammation stimulation of normal skin tissue-derived fibroblasts confirmed that the secretion of collagen was promoted, and showed properties similar to those of scleroderma patient-derived fibroblasts. Therefore, the inflammatory stimulus on healthy skin tissue-derived fibroblasts reproduces “collagen fiber hyperplasia by fibroblast activation” identified in scleroderma patient tissues.
  • mebendazole significantly suppresses the amount of collagen secreted in the culture supernatant (concentration dependent), and mebendazole appears specifically in scleroderma patient skin. It is suggested that it has an inhibitory effect on collagen fiber proliferation.
  • albendazole As shown in FIG. 13C, the addition of albendazole (ALZ) significantly suppresses the amount of collagen secreted in the culture supernatant, and albendazole is a collagen fiber specifically seen in scleroderma patient skin. It has been suggested that it has an inhibitory effect on hyperplasia of AZA
  • the most frequently used model animal is "a mouse with fibrotic foci formation caused by inflammation by intradermal administration of bleomycin (BLM)", but explored conditions that allow thickening and fibrosis equivalent to SSc patients Optimization was carried out to construct SSc disease model mice.
  • bleomycin was continuously administered subcutaneously daily at a dose of 1.5 mg / day (28 days).
  • the evaluation compound was administered to the mice receiving bleomycin under the following conditions.
  • As a control the same test was conducted on mice that received 0.5% (w / w) aqueous solution of CMC (carboxymethylcellulose) alone.
  • Skin tissues were collected 28 days after the initiation of bleomycin administration, and formalin fixed paraffin blocks were prepared. These tissue samples were deparaffinized by treating with xylene 5 minutes ⁇ 3 times, 100% ethanol 1 minute ⁇ 2 times, 90% ethanol 1 minute, 80% ethanol 1 minute, 70% ethanol 1 minute, water 5 minutes . Staining was performed with Meyer's hematoxylin solution for 4 minutes and eosin solution for 1 minute. Treated in running water for 5 minutes, treated with 70% ethanol 1 minute, 80% ethanol 1 minute, 90% ethanol 1 minute, 100% ethanol 1 minute ⁇ 2 times, xylene 5 minutes ⁇ 3 times, using marinol Sealed. After drying at room temperature for 15 minutes or more, observation was performed using an optical microscope.
  • epalrestat significantly suppressed BLM-induced skin thickening (concentration dependent), confirming the therapeutic efficacy of epalrestat against SSc using SSc model mice. .
  • Bleomycin (BLM) -induced scleroderma model construction 150 ml of Bleomycin (Bleo) dissolved in saline (NaCl) at 1 mg / ml on the back of 8- to 10-week-old female C57BL / 6J wild-type mice Every day for 4 weeks, it was injected subcutaneously to induce scleroderma foci of skin hardening due to fibrosis.
  • Oral administration of Compound A At 40 mg / kg or 80 mg / kg of Compound A (: LG283) dissolved in polyethylene glycol was orally administered daily at the same time as Bleo administration (evaluation test group), and compared with placebo group to which only polyethylene glycol was administered.
  • inflammation causes the transformation of fibroblasts in the dermis, and the secretion of matrix molecules such as (1) collagen and (2) Fibronectin is enhanced, resulting in the formation of fibrotic foci in the cell dermis.
  • matrix molecules such as (1) collagen and (2) Fibronectin
  • TGF- ⁇ 1 The action of TGF- ⁇ 1 on human normal cultured dermal fibroblast HFFF induced transformation, and the expression (mRNA) of collagen Collagen 1A2 and Fibronectin 1 was enhanced (quantified by qRT-PCR). By acting on this compound A (4.5 ⁇ M), the expression (mRNA) of collagens Collagen 1A2 and Fibronectin 1 was significantly suppressed (FIG. 20).
  • TGF- ⁇ 1 acts on human normal cultured skin fibroblasts HFFF, transformation is induced and the expression level of collagen Collagen 1A2 protein is enhanced (evaluated by Western Blotting). By acting on this compound A (4.5 ⁇ M), the expression of collagen collagen 1A2 protein was significantly suppressed (FIG. 21).
  • Compound A suppresses the expression of matrix molecules of (1) collagen and (2) fibronectin involved in fibrotic foci formation of scleroderma at gene expression level (experiment A) and protein secretion level (experiments B and C) It was confirmed that Compound A was effective in treating scleroderma.
  • the present invention is useful as a therapeutic and / or prophylactic agent for systemic scleroderma.

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Abstract

La présente invention concerne une composition pharmaceutique pour traiter ou prévenir la sclérodermie systémique, la composition contenant un composé qui supprime l'activation de cellules fibroblastiques dans des tissus dérivés du derme.
PCT/JP2018/045053 2017-12-08 2018-12-07 Agent thérapeutique de la sclérodermie systémique WO2019112031A1 (fr)

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JP2009513520A (ja) * 2003-07-08 2009-04-02 イーエムテーエム ゲーエムベーハー 線維芽細胞の過剰増殖および分化状態の変化を含む皮膚疾患の治療ならびに予防のための、アミノペプチダーゼｎおよび／またはジペプチジルペプチダーゼｉｖの活性を有する酵素の阻害剤の使用、ならびにそれらを含有する医薬調製品の使用
US20100093613A1 (en) * 2007-03-09 2010-04-15 Kunkel Eric J Methods for identifying agents and their use for the prevention or stabilization of fibrosis
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2021387517B2 (en) * 2020-11-30 2024-02-15 Innovo Therapeutics Inc. Pharmaceutical composition for preventing or treating wound or scar, comprising benzbromarone
US11951089B2 (en) 2020-11-30 2024-04-09 Innovo Therapeutics Inc. Pharmaceutical composition for preventing or treating wound or scar, comprising benzbromarone

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